Three dimensional electrospun biomedical patch for facilitating tissue repair

ABSTRACT

A three-dimensional electrospun biomedical patch includes a first polymeric scaffold having a first structure of deposited electrospun fibers extending in a plurality of directions in three dimensions to facilitate cellular migration for a first period of time upon application of the biomedical patch to a tissue, wherein the first period of time is less than twelve months, and a second polymeric scaffold having a second structure of deposited electrospun fibers. The second structure of deposited electrospun fibers includes the plurality of deposited electrospun fibers configured to provide structural reinforcement for a second period of time upon application of the three-dimensional electrospun biomedical patch to the tissue wherein the second period of time is less than twelve months. The three-dimensional electrospun biomedical patch is sufficiently pliable and resistant to tearing to enable movement of the three-dimensional electrospun biomedical patch with the tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/381,792, filed Jul. 21, 2021, which is a continuation of U.S. patentapplication Ser. No. 17/229,226, now U.S. Pat. No. 11,173,234, filedApr. 13, 2021, which is a continuation of U.S. patent application Ser.No. 16/872,926, filed May 12, 2020, which is a continuation of U.S.patent application Ser. No. 16/540,779, now U.S. Pat. No. 10,682,444,filed Aug. 14, 2019, which is a continuation of U.S. patent applicationSer. No. 16/131,887, now U.S. Pat. No. 10,441,685, filed Sep. 14, 2018,which is a divisional of U.S. patent application Ser. No. 14/429,976,now U.S. Pat. No. 10,124,089, filed Mar. 20, 2015, which areincorporated herein in their entirety. U.S. patent application Ser. No.14/429,976 is a U.S. National Phase Patent Application of InternationalApplication Serial Number PCT/US2012/056548, filed Sep. 21, 2012, whichis incorporated herein in its entirety.

BACKGROUND

Numerous pathological conditions and surgical procedures result insubstantial defects in a variety of organs, tissues, and anatomicalstructures. In the majority of such cases, surgeons and physicians arerequired to repair such defects utilizing specialized types of surgicalmeshes, materials, and/or scaffolds. Unfortunately, the in vivoperformance of known surgical materials is negatively impacted by anumber of limiting factors. For instance, existing synthetic surgicalmeshes typically result in excessive fibrosis or scarification leadingto poor tissue integration and increased risk of post-operative pain.Simultaneously, known biologic materials may induce strong immunereactions and aberrant tissue ingrowth which negatively impact patientoutcomes. Additionally, existing synthetic surgical meshes can createscarification, post-operative pain, limited mobility, limited range ofmotion, adhesions, infections, erosion, poor biomechanical properties,and/or poor intraoperative handling.

Nanofabricated or nanofiber meshes or materials composed of reabsorbablepolymer fibers tens to thousands of times smaller than individual humancells have recently been proposed as a unique substrate for implantablesurgical meshes and materials. Generally, existing nanofiber materialstend to possess suboptimal mechanical performance compared to knownsurgical meshes. Existing nanofiber materials do not possess the tensilestrength, tear resistance, and burst strength needed for numeroussurgical applications or for basic intraoperative handling prior to invivo placement. To combat this deficiency, known meshes are formed usinghigher fiber densities as a means of improving mechanical strength. Yet,utilization of such high-density meshes can decrease effective cellularingrowth into the mesh, decrease mesh integration with native tissue,and reduce the biocompatibility of the polymeric implant. As a result,nanofiber materials with increased thickness and/or strength andfavorable cellular and/or tissue integration and biocompatibility isneeded as well as a method for producing nanofiber materials.

SUMMARY

A three-dimensional electrospun nanofiber scaffold for use in repairinga defect in a tissue substrate is provided. The three-dimensionalelectrospun nanofiber scaffold includes a first layer formed by a firstplurality of electrospun polymeric fibers and a second layer formed bya. second plurality of electrospun polymeric fibers. The second layer iscoupled to the first layer using a coupling process and includes aplurality of varying densities formed by the second plurality ofelectrospun polymeric fibers. The first and second layers are configuredto degrade via hydrolysis after at least one of a predetermined time oran environmental condition. The three-dimensional electrospun nanofiberscaffold is configured to be applied to the tissue substrate containingthe defect.

A three-dimensional electrospun nanofiber scaffold for use in repairinga defect in a tissue substrate is provided. The three-dimensionalelectrospun nanofiber scaffold includes a first plurality of electrospunpolymeric fibers and a second plurality of electrospun polymeric fibers.The second plurality of electrospun polymeric fibers are coupled to thefirst plurality of electrospun polymeric fibers using a coupling processand form a plurality of varying densities within the three-dimensionalelectrospun nanofiber scaffold. The first plurality of electrospunpolymeric fibers and the second plurality of electrospun polymericfibers are configured to separate after at least one of a predeterminedtime or an environmental condition. The three-dimensional electrospunnanofiber scaffold is configured to be applied to the tissue substratecontaining the defect.

A biomedical patch for use in repairing a defect in a tissue substrateis provided. The biomedical patch includes a first plurality ofelectrospun polymeric fibers and a second plurality of electrospunpolymeric fibers. The second plurality of electrospun polymeric fibersare coupled to the first plurality of electrospun polymeric fibers usinga coupling process and form a plurality of varying densities within thebiomedical patch. The first plurality of electrospun polymeric fibersand the second plurality of electrospun polymeric fibers are configuredto separate after at least one of a predetermined time or anenvironmental condition. The biomedical patch is configured to beapplied to the tissue substrate containing the detect.

BRIEF DESCRIPTION OF THE DRAWINGS

The embodiments described herein may be better understood by referringto the following description in conjunction with the accompanyingdrawings.

FIG. 1 is a diagram illustrating an electrospinning system for producinga structure of spatially arranged fibers.

FIG. 2 is a diagram of a collector removed from the electrospinningsystem of FIG. 1 and having a plurality of fibers deposited thereonforming a patch.

FIG. 3 is an illustration of a biomedical patch including a plurality ofspatially arranged electrospun fibers deposited on a collector shown inFIG. 1.

FIG. 4 is another illustration of a biomedical patch including aplurality of spatially arranged electrospun fibers deposited on acollector shown in FIG. 1.

FIG. 5 is an illustration of a solid fiber spinneret shown in FIG. 1.

FIG. 6 is an illustration of a co-axial fiber spinneret shown in FIG. 1.

FIG. 7 is an illustration of a multi-layer biomedical patch.

FIG. 8 is an illustration of a delamination of patches, such as thepatch shown in FIG. 7, using various fusion strengths over time.

FIGS. 9 and 10 are histological cross-sections of regenerated durarepaired with multi-laminar nanofiber material such as a patch shown inFIG. 8.

FIGS. 11 and 12 are histological cross-sections of regenerated durarepaired with multi-laminar nanofiber material such as a patch shown inFIG. 8.

FIG. 13 is an illustration of a delamination of patches, such as thepatch shown in FIG. 7, using various fusion methods and strengths overtime.

FIG. 14 is a flowchart of an exemplary method 700 for producing astructure of spatially arranged fibers using system 100 shown in FIG. 1.

FIG. 15 is a flowchart of an exemplary method 750 for fusing or couplingtogether structures or patch layers produced by method 700 shown in FIG.14.

FIG. 16 is a flowchart of an exemplary method 800 for repairing a defectin a biological tissue using the structures produced by methods 700 and750 shown in FIGS. 14 and 15.

DETAILED DESCRIPTION

Embodiments provided herein facilitate repairing biological tissue orreinforcing biomedical material with the use of a biomedical patchincluding a plurality of fibers. Such fibers may have a very smallcross-sectional diameter (e.g., from 1-3000 nanometers) and,accordingly, may be referred to as nanofibers and/or microfibers. Whilebiomedical patches are described herein with reference to dura mater anduse as a surgical mesh, embodiments described may be applied to anybiological tissue. Moreover, although described as biomedical patches,structures with aligned fibers may be used for other purposes.Accordingly, embodiments described are not limited to biomedicalpatches.

In operation, biomedical patches provided herein facilitate cell growth,provide reinforcement, and may be referred to as “membranes,”“scaffolds,” “matrices,” “meshes”, “implants”, or “substrates.”Biomedical patches with varying densities, as described herein, maypromote significantly faster healing and/or regeneration of tissue suchas the dura mater than existing patches constructed using conventionaldesigns.

Dura mater is a membranous connective tissue comprising the outermostlayer of the meninges surrounding the brain and spinal cord, whichcovers and supports the dural sinuses. Surgical meshes are often neededduring neurosurgical, orthopedic, or reconstructive surgical proceduresto repair, expand, reinforce, or replace the incised, damaged, orresected dura mater.

Although many efforts have been made, the challenge to develop asuitable surgical mesh for dural repair has been met with limitedsuccess. Autografts (e.g., fascia lata, temporalis fascia, andpericranium) are preferable because they do not provoke severeinflammatory or immunologic reactions. Potential drawbacks of autograftsinclude the difficulty in achieving a watertight closure, formation ofscar tissue, insufficient availability of graft materials to close largedural defects, increased risk of infection, donor site morbidity, andthe need for an additional operative site. Allografts and xenograftmaterials are often associated with adverse effects such as graftdissolution, encapsulation, foreign body reaction, immunologicalreaction, contracture, scarring, adhesion formation, andtoxicity-induced side effects from immunosuppressive regimens.Lyophilized human dura mater as a dural substitute has also beenreported as a source of transmittable diseases, specifically involvingprions, such as Creutzfeldt-Jakob disease.

In terms of synthetic surgical mesh materials, non-absorbable syntheticpolymers, such as silicone and expanded polytetrafluoroethylene (ePTFE),often cause serious complications that may include induction ofgranulation tissue formation due to their chronic stimulation of theforeign body response. Natural absorbable polymers, including collagen,fibrin, and cellulose, may present a risk of infection and diseasetransmission. As a result, synthetic absorbable polymers such as poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly (lactic acid)(PLA), polyglycolic acid (PGA), poly (lactic-co-glycolic acid) (PLGA),PLA-PCL-PGA ternary copolymers, and hydroxyethylmethacrylate hydrogelshave recently attracted attention as biodegradable implant materials fordural repair. Methods and systems described herein may be practiced withthese materials and/or any biomedical polymer whether the polymer isnon-absorbable or absorbable, or synthetic in origin.

In order to facilitate successful regeneration and/or repair of the duramater following surgery, a synthetic surgical mesh or biomedical patchshould promote: i) adhesion of dural fibroblasts (the primary cell typepresent in the dura) to the surface of the biomedical patch; ii)migration of dural fibroblasts from the periphery of the biomedicalpatch into the center of the patch; iii) reinforcement or replacement ofexisting tissues; iv) minimal immune response; v) water tight closure ofthe dural membrane/dura mater; vi) mechanical support of the nativedural post-operatively and during tissue regeneration/neoduralization;vii) rapid closure of the dural defect; and viii) increased ease of use.

Electrospinning is an enabling technique which can produce nanoscalefibers from a large number of polymers. The electrospun nanofibers aretypically collected as a randomly-oriented, nonwoven mat. Uniaxially orradially aligned arrays of nanofibers can also be obtained under certainconditions. However, traditional nanofiber scaffolds may lack theoptimal mechanical and biological properties necessary for somebiomedical or surgical applications post-operatively.

In order to increase the strength of nanofiber scaffolds, customfabrication of scaffolds into particular patterns would be highlyadvantageous. Additionally, multiple layers of nanofiber materialsfused/coupled together in a manner that allows for a purposefuldegradation of the layers can also provide strength while allowing forcellular penetration and/or tissue integration.

Many polymers are available for use in electrospinning. In someembodiments described herein, nanofibers for dura substitutes areproduced as the electrospun polymer from poly (ε-caprolactone) (PCL), anFDA approved, semicrystalline polyester that can degrade via hydrolysisof its ester linkages under physiological conditions with nontoxicdegradation products. This polymer has been extensively utilized andstudied in the human body as a material for fabrication of drug deliverycarriers, sutures, or adhesion barriers. As described herein,electrospun PCL nanofibers may be used to generate scaffolds that areuseful as surgical meshes.

Embodiments provided herein facilitate producing a novel type ofartificial tissue substitute including a polymeric nanofiber material,which is formed through a novel method of electrospinning. Thispolymeric material includes non-woven nanofibers (e.g., fibers having adiameter of 1-3000 nanometers) which are arranged or organized andaligned into patterns both within and across a material sheet.

FIG. 1 is a diagram illustrating a perspective view of an exemplaryelectrospinning system 100 for producing a structure of spatiallyarranged or organized fibers. System 100 includes a collector 105 with apredetermined pattern 110 including a plurality of reinforcementfeatures 112. System 100 also includes a spinneret 120.

System 100 is configured to create an electric potential between one ormore collectors 105 and one or more spinnerets 120. In one embodiment,collector 105 and features 112 are configured to be electrically chargedat a first amplitude and/or polarity. For example, collector 105 andfeatures 112 may be electrically coupled to one or more power supplies130 via one or more conductors 135. Power supply 130 is configured tocharge collector 105 and features 112 at the first amplitude and/orpolarity via conductor 135.

In the embodiment illustrated in FIG. 1, collector 105 includes pattern110 that is a grid pattern formed by features 112 such that collector105 is substantially rectangular. In other embodiments, collector 105may have any shape including, but not limited to, circular, elliptical,ovular, square, and/or triangular. In one embodiment, features 112include ribs 114, seams 116, and surfaces 118 configured to receiveand/or collect polymer fibers. In one embodiment, rib 114 issubstantially cylindrical and has a circumference between 5 um-100 cm,seam 116 is substantially rectangular having a thickness between 5um-100 cm, and surface 118 is a filling of a void or feature space 119formed between ribs 114 and/or seams 116. In one embodiment, surface hasa thickness between 5 um-10 cm. In the exemplary embodiment, features112 are made fabricated from at least a portion of metallic substance,including, but not limited to steel, aluminum, tin, copper, silver,gold, platinum, and any alloy or mixture thereof. In one embodiment,features 112 include a coating applied to collector 105. Coatings caninclude, but are not limited to anodization, chemical coatings, materialcoatings (conductive or non-conductive), and gradient coatings thatfacilitate the creation of continuous gradients of fibers. However, itshould be noted that features 112 (e.g., ribs 114, seams 116, andsurface 118) can have any shape and be fabricated from any material thatfacilitates producing patches as disclosed herein.

In the exemplary embodiment, pattern 110 is formed by spatiallyorganizing features 112. In one embodiment, features 112 (e.g., ribs 114and seams 116) are interconnected at nodes 115 such that a feature space119 is formed between features 112 in the range of 10 um and 10 cm. Inone embodiment, pattern 110 includes a plurality of spaces 119 such thatmultiple varying distances are formed between features 112. It should benoted that pattern can be formed to be symmetrical, repeating, andasymmetrical. In the exemplary embodiment, the shape of collector 105enables the biomedical patch formed on collector to include additionalsupport and/or reinforcement properties. Such additional support and/orreinforcement properties are achieved by creating high density fiberdeposition areas on charged features 112 and having low density fiberdeposition areas over feature spaces 119.

For example, a diamond shaped collector 105 including a diamond shapedarray pattern 110 enables a diamond-shaped patch to be produced on thediamond shaped collector 105 to have different mechanical propertiesfrom a rectangular-shaped or a circular-shaped patch such as, but notlimited to, tensile strength, tear resistance, terminal strain, failuremechanisms or rates, and/or controlled anisotropic properties, such asgreater strength in one axis relative to another.

In one embodiment, pattern 110 defines a collector plane 127 andspinneret 120 is orthogonally offset from the collector plane 127 at avariable distance. For example, spinneret 120 may be orthogonally offsetfrom the collector plane 127 at a distance of 50 micrometers to 100centimeters. Alternatively, spinneret 120 can be offset from collector105 in any manner that facilitates creating patches as described herein,including but not limited to, horizontal and diagonal or skew.

Spinneret 120 is configured to dispense a polymer 140 while electricallycharged at a second amplitude and/or polarity opposite the firstamplitude and/or polarity. As shown in FIG. 1, spinneret 120 iselectrically coupled to one or more power supplies 130 by one or moreconductors 145. Power supply 130 is configured to charge one or morespinnerets 120 at the second amplitude and/or polarity via conductor145. In some embodiments, power supplies 130 provides a direct currentand/or static or time variant voltage (e.g., between 1-50 kilovolts). Inone embodiment, conductor 145 is charged positively, and collector 105is also charged positively. In all embodiments, power supply 130 isconfigured to allow adjustment of a current, a voltage, and/or a power.

In one embodiment, spinneret 120 is coupled to a dispensing mechanism150 containing polymer 140 in a liquid solution form. In such anembodiment, dispensing mechanism 150 is operated manually by adispensing pump 155. Alternatively, dispensing mechanism 150 can beoperated automatically with any mechanism configured to dispensenanofibers as described herein. In the exemplary embodiment, spinneret120 includes a metallic needle having an aperture between 10 micrometersand 3 millimeters in diameter for dispensing nanofibers.

As dispensing mechanism 150 pressurizes polymer 140, spinneret 120dispenses polymer 140 as a jet or stream 160. In one embodiment, stream160 is dispensed in a horizontal or sideways stream from spinneret 120.Stream 160 has a diameter approximately equal to the aperture diameterof spinneret 120. Stream 160 descends toward collector 105 forming aTaylor cone. For example, stream 160 may fall downward under theinfluence of gravity and/or may be attracted downward by chargedistributed on the fibers and on features 112. As stream 160 descends,polymer 140 forms one or more solid polymeric fibers 165. In theexemplary embodiment, fibers 165 are solid, however it should be notedthat fibers 165 can have any structure including by not limited to, coreor shell, porous, co-axial, and co-axial. Alternatively, polymer 140deposition can be accomplished by any other fiber deposition methodincluding but not limited to, solvent electrospinning, forceelectrospinning, melt electrospinning, extrusion, and melt blowing.

In some embodiments, a mask 164 composed of a conducting ornon-conducting material is applied to collector 105 to manipulatedeposition of fibers 165. For example, mask 164 may be positionedbetween spinneret 120 and collector 105 such that no fibers 165 aredeposited on collector 105 beneath mask 164. Moreover, mask 164 may beused as a time-variant mask by adjusting its position between thespinneret and the collector while spinneret 120 dispenses polymer 140,facilitating spatial variation of fiber density on collector 105. Whilemask 164 is shown as circular, mask 164 may have any shape (e.g.,rectangular or semi-circular) and size suitable for use with system 100.Alternatively, or in addition, deposition of fibers 165 on collector 105may be manipulated by adjusting the position of collector 105 withrespect to spinneret 120 or by spatially varying the electricalpotential applied between the spinneret 120 and/or the electrodes makingup the collector 105. For example, positioning one side of collector 105directly beneath spinneret 120 may cause more fibers 165 to be depositedon that side than are deposited on the opposite side of collector 105 ina Gaussian distribution. To modulate the spatial distribution of fibersforming on collector 105, in some embodiments, a focusing device 138 isutilized to focus fiber deposition in a particular special region. Insuch an embodiment, focusing device 138 is charged with a polaritysimilar to spinneret 120 and includes an aperture allowing fiberdeposition to occur substantially in the space under the aperture.Focusing device 138 may have any geometry that allows for receipt ofnanofibers from spinneret 120 and deposition of the received nanofibersonto collector 105 as described herein.

FIG. 2 is a diagram of collector 105 removed from electrospinning system100 (shown in FIG. 1) and having a plurality of fibers 165 depositedthereon forming a patch 170. Fibers 165 are oriented such that theycorrespond to the position of features 112 (shown in FIG. 1).

Patch 170 is illustrated with a small quantity of fibers 165 in FIG. 2for clarity. In some embodiments, patch 170 includes thousands, tens ofthousands, hundreds of thousands, or more fibers 165, distributed oncollector 105. Even with millions of fibers 165, patch 170 retainspredictable properties such as being flexible and/or pliable. As such,the predictable properties facilitate the application of patch 170 touneven biological tissue surfaces, such as the surface of the duramater.

The alignment of fibers 165 illustrates a patch 170 with varyingdensities. Patch 170 enables reinforcement or structural integrity to beprovided in predetermined locations. For example, a larger deposition offibers occurs in various locations, such as portion 167, which providestructural reinforcement. Accordingly, system 100 enables the creationof customized materials 170 for individual biomedical or clinical andnon-clinical applications.

In the exemplary embodiment, fibers 165 have a diameter of 1-3000nanometers. In one embodiment, fibers have a diameter of approximately220 nanometers (e.g., 215 nm to 225 nm). It should be noted that thediameter of the fibers 165, thickness of the patch 170, and/or fiberdensity within the patch 170 may affect the durability (e.g., tensilestrength, suture pullout strength, conformability, etc.) of patch 170.As such, the diameter of the fibers 165, thickness of the patch 170,and/or fiber density within the patch 170 can be selected according tothe requirements of the end application of the material. Patch 170 maybe produced with various mechanical properties by varying the thicknessand/or the fiber density, spatial patterning, polymer composition,and/or number of layers of the patch 170 by operating electrospinningsystem 100 for relatively longer or shorter durations, changing thepolymeric solution, changing the chemical composition, changingcollector 105, changing collector design, and/or changing the manner offiber deposition.

FIG. 3 is an illustration 305 of a patch 170 including a plurality ofelectrospun fibers deposited on collector 105 and FIG. 4 is anillustration 405 of a patch 170 including a plurality of electrospunfibers deposited on collector 105. In the exemplary embodiment,collectors 105 respectively provide an increased deposition of fibers onand substantial near features 112. Such additional support and/orreinforcement properties are achieved by creating high density fiberdeposition areas on charged features 112 and having low density fiberdeposition areas over feature spaces 119. It should be noted thatcollector 105 can include any pattern or combination of patterns such asthe grid pattern shown in FIG. 3 and the hexagonal or honeycomb patternshown in FIG. 4.

Referring to FIGS. 1-4, fibers 165 may be solid, core/shell, co-axial,or porous. In some embodiments, the size and/or structure of fibers 165is determined by the design and/or size of spinneret 120, and/or polymersolution which includes viscosity, solvent or method of preparation ofthe solution, voltage or electric charge, distance between spinneret 120and collector 105, and rate of deposition. FIG. 5 is an illustration ofa solid fiber spinneret 120A. Solid fiber spinneret 120A includes atruncated conical body 180 defining a center line 182. At a dispensingend 184, body 180 includes an annulus 186. Annulus 186 defines acircular aperture 190A, through which polymer 140 may be dispensed.Fibers 165 produced with solid fiber spinneret 120A have a solidcomposition.

FIG. 6 is an illustration of a co-axial fiber spinneret 120B. Like solidfiber spinneret 120A, co-axial fiber spinneret 120B includes a truncatedconical body 180 with an annulus 186 at a dispensing end 184. Co-axialfiber spinneret 120B also includes a central body 188B positioned withinannulus 186. Annulus 186 and central body 188B define an annularaperture 190B. Accordingly, when polymer 140 is dispensed by co-axialfiber spinneret 120B, fibers 165 have a co-axial composition, with anexterior wall surrounding a cavity. The exterior wall of a fiber 165dispensed by co-axial fiber spinneret 120B defines an outer diametercorresponding to the inner diameter of annulus 186 and an inner diametercorresponding to the diameter of central body 188B. Accordingly, theouter diameter and inner diameter of co-axial fibers 165 may be adjustedby adjusting the diameters of annulus 186 and central body 188B.

Fiber spinnerets 120A and 120B facilitate incorporating a substance,such as a biological agent, growth factor, and/or a drug (e.g., achemotherapeutic substance), into patch 170. For example, the substancemay be deposited within a cavity defined by co-axial fibers 165 of patch170. In one embodiment, polymer 140 is selected to create porous and/orsemi-soluble fibers 165, and the substance is dispensed from the cavitythrough fibers 165. In another embodiment, polymer 140 is degradable,and the substance is dispensed as fibers 165 degrade in vivo. Forexample, fibers 165 may be configured to degrade within a second to 1second to 12 months. In one embodiment, a burst release of the substanceoccurs upon entry into a system and an elution occurs over apredetermined period of time. The degradation rate of polymer 140 may bemanipulated by any loading and/or release method such as adjusting aratio of constituent polymers within polymer 140, loading the agent intothe bulk of the material, functionalizing the agent to the surface ofthe fibers, and/or releasing the agent by degradation of the polymer orby diffusion of the agent from the polymer. In another embodiment, asubstance is delivered by solid fibers 165. For example, a solid fiber165 may be created from a polymer 140 including the substance insolution. As solid fiber 165 degrades, the substance is released intothe surrounding tissue.

As shown in FIGS. 5 and 6, annulus 186 is perpendicular to center line182. In an alternative embodiment, annulus 186 is oblique (e.g.,oriented at an acute or obtuse angle) with respect to center line 182.The outside diameter of fibers 165 may be determined by the insidediameter of annulus 186.

FIG. 7 is an illustration of a multi-layer biomedical patch 435. Patch435 includes a biomedical patch layer with a plurality of symmetricalspatially organized fibers 420 and a biomedical patch layer with aplurality of spatially organized fibers having varying densities 425such as increased density portions 430. As shown in FIG. 7, biomedicalpatch layers 420 and 425 are combined (e.g., fused, joined, adhered,overlaid) to produce multi-layer biomedical patch 435 with reinforcementfiber layers. It should be noted that any combination, number, or typeof fiber layers may be combined to create biomedical patch 435.Combining the patches, especially layers 420 and 425, facilitatesproviding a biomedical patch that promotes cell migration to a center ofthe biomedical patch while exhibiting potentially greater durability(e.g., tensile strength) than a biomedical patch having only standard,randomly-organized fibers. It should be noted that patch 435 can beformed of layers having various densities and/or thicknesses (bothindividually and collectively), fiber organizations, polymercompositions, surface coatings, and types of concentrations of agentsand/or drugs.

In some embodiments, multiple biomedical patch layers 410-425 may becombined to create a multi-layer biomedical patch. For example,referring to FIGS. 1-4, after depositing a first set of fibers oncollector 105, one may wait for the first set of fibers 165 to solidifycompletely or cure and then deposit a second set of fibers 165 oncollector 105. The second set of fibers 165 may be deposited directlyover the first set of fibers 165 on collector 105. Alternatively, thefirst set of fibers 165 may be removed from collector 105, and thesecond set of fibers 165 may be deposited on conductive surface 162and/or collector 105 and then removed and adhered/overlaid on the firstset of fibers 165. Such embodiments facilitate increased structural ormechanical reinforcement of the patch in predetermined locations, andadded spatial control of cell migration/activity imparted by the layers2-dimensionally and stacked layers 3-dimensionally. In some embodiments,a non nanofiber intermediate layer (e.g., hydrogel or polymericscaffold) may be disposed between biomedical patch layers 400 and/orbiomedical patch layers 410.

In the exemplary embodiment, individual layers are fused or coupledtogether such that the layers delaminate or separate under specificenvironmental or temporal conditions. Such controlled delaminationresults in maximization of mechanical stability of the nanofibermaterial and the biological interaction (e.g. cellular ingrowth, tissueintegration, cellular exposure, etc.) between adjacent layers ofnanofibers. In the exemplary embodiment, the process of fusing orcoupling layers includes, but is not limited to, heating, applyingmechanical stress/pressure, applying an adhesive, chemical processing,cross-linking, and functionalization.

In one embodiment, adjacent layers are similarly or variably fused,adhered, or joined such that each layer delaminates or separates at asubstantially similar rate within patch 435. Alternatively, layers canbe fused together with variable methods such that each layer delaminatesat different rates. FIG. 8 illustrates delamination of patches 440, 445,and 450 with various fusion strengths over time. In the exemplaryembodiment, a low strength adhesion 455, such as but not limited tomild-chemical treatment or crosslinking, low-pressure physicallamination, or low-temperature thermal processing, is used to fuselayers of patch 440 together. Similarly, a moderate strength adhesion460 such as but not limited to moderate chemical crosslinking, prolongedthermal processing, moderate mechanical entanglement, application ofmoderate adhesives, or high-pressure physical lamination is used to fusethe layers of patch 445 and a high strength adhesion 465, such as butnot limited to extensive chemical crosslinking, extensivehigh-temperature thermal processing, extensive mechanical entanglement,fiber interweaving or knitting, or application of aggressive adhesivesis used to fuse layers of patch 450 together. In the exemplaryembodiment, a separation 470 of patches 440, 445, and 450 is shown aftera short increment of time, such as, but not limited to 1 day-30 days anda separation 475 of patches 440, 445, and 450 is shown after a longincrement of time, such as, but not limited to 30 days-3 years. As isshown, patch 440 is substantially separated 470 after a short period oftime acting as an accelerated separation, patch 445 is substantiallyseparated 475 after the long period of time acting as a delayedseparation, and patch 450 provided substantially no separation.

FIGS. 9 and 10 are histological cross-sections 500 and 502 of dura materrepaired with multi-laminar nanofiber material such as patch 440 shownin FIG. 8. Referring to FIG. 9, patch 440 is shown as being insertedinto dura 504 two weeks post-operatively. Regenerative dural tissue(“neodura”) 504 is demonstrated extending on and around the implantednanofiber material 440. Regenerative dural fibroblasts are also shown tohave penetrated the bulk of the nanofiber material 440, demonstratingprogressive cellularization of the implanted nanofiber construct. Twoweeks following implantation of the multi-layer nanofiber material 440no delamination is noted upon histological examination of the explantedtissue. The nanofiber material 440 is observed as a homogeneous block ofmaterial with low to moderate cellular ingrowth, yet no singularnanofiber layer or separation of nanofiber layers is observed. FIG. 10illustrates controlled delamination of patch 440 six weekspost-operatively and integration of the patch within the native and/orregenerated dural tissue 504. Regenerative dural tissue (“neodura”) 504is demonstrated extending on and around the implanted nanofiber material440. Additionally, regenerative dural tissue (“neodura”) is demonstratedextending in between delaminated layers of the nanofiber material.Regenerative dural fibroblasts are shown to have significantlypenetrated the bulk of the nanofiber material 440, demonstrating robustcellularization and integration of the implanted nanofiber construct.Delamination of individual layers of nanofibers within the implantconstruct is noted upon histological examination of the explantedtissue. The nanofiber material 440 is observed as two heterogeneouslayers of material separated by a thin layer of regenerated dural tissueextending along the adjoining surface of the nanofiber monolayers.Evidence of controlled delamination of the implanted materialpost-operatively is specifically demonstrated by observation thatmultiple layers of the material remain fused in proximity of suturesutilized to secure the material to the native tissue.

FIGS. 11 and 12 are histological cross-sections 506 and 508 ofregenerated dura repaired with multi-laminar nanofiber material such aspatch 450 shown in FIG. 8. Referring to FIG. 11, patch 450 is shown asbeing inserted into dura 504 two weeks post-operatively. Regenerativedural tissue (“neodura”) 504 is demonstrated extending on and around theimplanted nanofiber material 450. Regenerative dural fibroblasts arealso shown to have penetrated the bulk of the nanofiber material 450,demonstrating cellularization of the implanted nanofiber construct. Nodelamination is noted upon histological examination of the explantedtissue. The nanofiber material 450 is observed as a homogeneous block ofmaterial with low to moderate cellular ingrowth, yet no singularnanofiber layer or separation of nanofiber layers is observed. FIG. 12illustrates that the high strength adhesion has enabled layers of patch450 to remain substantially fused together six week post-operatively asdural tissue 504 regenerated around patch 450. Regenerative dural tissue(“neodura”) 504 is again demonstrated extending on and around theimplanted nanofiber material 450. Dural fibroblasts substantiallypenetrate the bulk of the nanofiber material 450, demonstrating robustcellularization of the implanted nanofiber construct. Unlike nanofiberpatch 440, no delamination of nanofiber patch 450 is noted uponhistological examination of the explanted tissue following chronicimplantation. The nanofiber material 450 is observed as a securecomposite material demonstrating cellular ingrowth yet no separation orobservation of singular nanofiber layers.

FIG. 13 illustrates separation of layers within patches 600, 602, and604 at varying rates. Each patch 600, 602, and 604 includes a firstlayer 606, a second layer, 608, a third layer 610, and a fourth layer612. It should be noted that while patches 600, 602, and 604 are shownwith four layers, patches can be fabricated to have any number oflayers. Referring to patch 600, low strength adhesion 455 is used tofuse layers 606, 608, and 610 together and high strength adhesion 465 isused to fuse layers 610 and 612 together. After a short time period, aseparation 614 of layers 606, 608, and 610 has occurred and layersremain substantially fused together. As shown in patch 602, moderatestrength adhesion 460 is used to fuse together layers 606 and 608, whilehigh strength adhesion 465 is used to fuse together layers 608, 610, and612. A separation 616 of layers 606 and 608 occurs after a long periodof time while substantially no separation occurs between layers 608,610, and 612. Referring to patch 604, a high strength adhesion 465 isused between layers 606, 608, 610, and 612 such that substantially noseparation occurs between the layers.

A multi-layered biomedical patch may be useful for dural grafts as wellas other tissue engineering applications. Sequential layers of fiberscan be created with varying orders (e.g., radially aligned, reinforced,or randomly oriented), densities (e.g., low, high, or mixture of fiberdensity), patterns or reinforcement, and compositions (polymer), whichmay allow specific types of cells to infiltrate and populate selectlayers of the artificial biomedical patch. For example, biomedicalpatches containing a high fiber density generally prohibit cellularmigration and infiltration, while biomedical patches containing a lowfiber density generally enhance cellular migration and infiltration.Such additional support and/or reinforcement properties are achieved bycreating high density fiber deposition that discourages cellularpenetration and having low density fiber deposition areas that promotecellular penetration and/or ingrowth.

Overall, the ability to form multi-layered fiber materials, as describedherein, may be extremely beneficial in the construction of biomedicalpatches designed to recapitulate the natural multi-laminar structure ofnot only dura mater, but also other biological tissues such as skin,heart valve leaflets, pericardium, and/or any other biological tissue.Furthermore, one or more layers of a biomedical patch may be fabricatedfrom bioresorbable polymers such that the resulting nanofiber materialsfully resorb following implantation. Manipulation of the chemicalcomposition of the polymers utilized to fabricate these scaffolds mayfurther allow for specific control of the rate of degradation and/orresorption of a biomedical patch following implantation.

FIG. 14 is a flowchart of an exemplary method 700 for producing astructure of spatially organized fibers using system 100 shown inFIG. 1. While one embodiment of method 700 is shown in FIG. 14, it iscontemplated that any of the operations illustrated may be omitted andthat the operations may be performed in a different order than is shown.In the exemplary embodiment, method 700 includes electrically charging705 collector 105 at a first amplitude and/or polarity (e.g., negativelycharging or grounding). Spinneret 120 is electrically charged 710 at asecond amplitude and/or polarity opposite the first amplitude and/orpolarity (e.g., positively charged). A polymer (e.g., a liquid polymer)is dispensed 715 from spinneret 120. In the exemplary embodiment,dispensed 715 polymers are collected 720 on collector 105 to form aplurality of polymeric fibers on or substantially near features 112 thatcreates a structure or patch. After the dispensed 615 polymers arecollected 720 and a structure is created, the structure may undergopost-processing 725. Such post-processing 725 can include, but is notlimited to, lamination, layer stacking, coupling and/or fusing,chemically treating, and applying a biological agent, growth factor,and/or drug.

FIG. 15 is a flowchart of an exemplary method 750 for fusing or couplingtogether structures or patch layers produced by method 700 shown in FIG.14. Method 750 includes providing 755 a first, second, and third patchlayer. First patch layer is coupled 760 to second patch layer using afirst coupling technique. The coupled 760 first and second layers arethen coupled 765 to the third patch layer using a second couplingtechnique different than the first coupling technique. In the exemplaryembodiment, coupling techniques, include but are not limited to,heating, applying mechanical stress/pressure, chemical processing,cross-linking, and functionalization. While method 750 illustrates afirst patch layer coupled to a second patch layer, it should be notedthat multiple layers (e.g., 3, 5, 6,) can be coupled togethersimultaneously. Additionally, the process may be repeated to add layersto structures produced by method 750.

FIG. 16 is a flowchart of an exemplary method 800 for repairing a defectof a substrate using a structure produced by methods 700 and 750 shownin FIGS. 14 and 15. In one embodiment, method 800 includes providing 805a substrate substance with a defect. The defect may include a void,tissue defect, injury, insult, and/or any other condition resulting indiminished function of biological tissue. In the exemplary embodiment,the substrate is biological tissue. Alternatively, the substrate can beany substrate including but not limited to, filtration media, textiles,membrane media, and coatings. In one embodiment, the defect provided 805includes a void created by surgical incision to provide access to anunderlying tissue (e.g., a tumor). In another embodiment, a void iscreated 805 by excising necrotic tissue (e.g., skin cells). In theexemplary embodiment, one or more patches capable of covering the defectare selected 810. For example, a plurality of biomedical patches may beselected 810 for a large and/or complex (e.g., irregularly shaped)defect. In the exemplary embodiment, a biomedical patch having adiameter greater than the diameter of an approximately circular defectis selected 810. Alternatively, a patch is selected 810 and customized,pre-operation or intra-operation, to fit the defect. It should be notedthat any size, shape, and/or geometry of structure may be used in theselection 810 of the patch.

In one embodiment, a substance such as a growth factor and/or a drug(e.g., a chemotherapeutic drug) is applied 815 to the biomedical patch.In the exemplary embodiment growth factor and/or a drug is applied 815pre-operatively. However, it should be noted that growth factor and/or adrug may be applied 815 at any time including, but not limited to,intra-operatively and post-operatively. In one embodiment, thebiomedical patch may be immersed in the substance to allow the substanceto occupy a cavity within co-axial fibers of the biomedical patch, dopethe polymer comprising the fibers in the biomedical patch, or coat thesurface of the fibers within the biomedical patch.

In the exemplary embodiment, the patch is applied 820 to (e.g., overlaidon) the biological tissue to cover, repair, reinforce, and/or fill atleast a portion of the defect. For example, the biomedical patch may beapplied 820 to dura mater tissue, cardiac tissue, and/or any biologicaltissue including a defect. In one embodiment, the perimeter of thebiomedical patch extends past the perimeter of the defect, such that theentire defect is covered by the biomedical patch. In some embodiments,the biomedical patch is coupled 825 to the biological tissue with aplurality of sutures, adhesive, and/or any other means of attaching thebiomedical patch to the biological tissue (inlay). In an alternativeembodiment, the biomedical patch is simply allowed to fuse to thebiological tissue, such as by adhesion of biological cells to thebiomedical patch (onlay). In another embodiment, biomedical patch may bedirectly coupled to the edge of the tissue with no overlap. In oneembodiment, biomedical patch may be overlaid on top of a wound/defect orinjury covering the entirety of the defect or injury without filling thedefect.

In one embodiment, after the biomedical patch is applied 820 andoptionally coupled 825 to the biological tissue, the biological tissueis covered 830. Alternatively, the patch may be the terminal covering.In such an embodiment, a backing that is either non-permeable orpermeable may be coupled to the patch. In one embodiment, other tissueoverlaying the defect (e.g., dermis and/or epidermis) is repaired (e.g.,sutured closed). In another embodiment, one or more protective layersare applied over the biological tissue. For example, a bandage may beapplied to a skin graft, with or without a protective substance, such asa gel, an ointment, and/or an antibacterial agent. In one embodiment,the protective layer includes, but is not limited to, a covering, filmtissue, dressing, mesh, and nanofiber structure, such as an additionalbiomedical patch, as described herein.

Embodiments described herein are operable with any surgical procedureinvolving the repair, replacement, or expansion of the dura mater,including, but not limited to, a transphenoidal procedure (e.g.,surgical removal of pituitary adenomas), various types of skull basesurgeries, and/or surgical removal of cranial or spinal tumors (e.g.,meningiomas and/or astrocytomas). In one embodiment, a biomedical patchmay be applied to a bone fracture (e.g., a complex fracture). In anotherembodiment, a biomedical patch may be applied to a defect in the skin(e.g. a burn).

Moreover, such embodiments provide a dura mater substitute, a biomedicalpatch for a skin graft (e.g., dermal or epidermal), a biomedical patchfor tracheal repair, a scaffold for an artificial heart valve leaflet,an artificial mesh for surgical repair of a gastrointestinal tract(e.g., an abdominal hernia or an ulcer), an artificial mesh for surgicalrepair of cardiac defects. Embodiments described herein facilitateproviding a cardiac patch of sufficient flexibility to enable movementof the biomedical patch by a biological tissue (e.g., cardiomyocytes orcardiac tissue, muscle, skin, connective tissue, intestinal tissue,stomach tissue, bone, gastrointestinal tract, and mucosa).

In some embodiments, a biomedical patch has a thickness greater or lessthan a thickness of the biological tissue being repaired. Biomedicalpatches with spatially organized polymeric fibers facilitate reducingthe expense of tissue repair, improving tissue healing time, andreducing or eliminating the risk of zoonotic infection. Moreover, suchbiomedical patches are relatively simple to manufacture, enablingcustomization of shape, size, and chemical composition and improvedavailability and non-immunogenicity. In addition, biomedical patcheswith spatially organized polymeric fibers exhibit excellent handlingproperties due to their cloth-like composition, eliminate the need for asecond surgery to harvest autologous graft tissue, and reduce the riskof contracture and adhesion when compared with known products.Additionally, the patches described herein facilitate reinforcement,buttressing, lamination, and/or sealing in a variety of applicationssuch as but not limited to clinical and non-clinical applications.

Although the foregoing description contains many specifics, these shouldnot be construed as limiting the scope of the present disclosure, butmerely as providing illustrations of some of the presently preferredembodiments. Similarly, other embodiments of the invention may bedevised which do not depart from the spirit or scope of the presentinvention. For example, while the illustrative examples have been usedin with clinical applications, the above described nanofiber structurescan have non-clinical application such as filtration, textiles, membranetechnology, and coatings. Features from different embodiments may beemployed in combination. The scope of the invention is, therefore,indicated and limited only by the appended claims and their legalequivalents, rather than by the foregoing description. All additions,deletions, and modifications to the invention as disclosed herein whichfall within the meaning and scope of the claims are to be embracedthereby.

As used herein, an element or step recited in the singular and proceededwith the word “a” or “an” should be understood as not excluding pluralelements or steps, unless such exclusion is explicitly recited.Furthermore, references to “one embodiment” of the present invention arenot intended to be interpreted as excluding the existence of additionalembodiments that also incorporate the recited features.

This written description uses examples to disclose various embodiments,which include the best mode, to enable any person skilled in the art topractice those embodiments, including making and using any devices orsystems and performing any incorporated methods. The patentable scope isdefined by the claims, and may include other examples that occur tothose skilled in the art. Such other examples are intended to be withinthe scope of the claims if they have structural elements that do notdiffer from the literal language of the claims, or if they includeequivalent structural elements with insubstantial differences from theliteral languages of the claims.

1-30. (canceled)
 31. A three-dimensional electrospun biomedical patch for facilitating tissue repair, the three-dimensional electrospun biomedical patch comprising: a first polymeric plurality of fibers making up a scaffold, the scaffold comprising a first structure of deposited electrospun fibers, the first structure of deposited electrospun fibers comprising a plurality of deposited electrospun fibers extending in a plurality of directions in three dimensions to facilitate cellular migration for a first period of time upon application of the three-dimensional electrospun biomedical patch to a tissue, wherein the first period of time is less than twelve months; a second polymeric plurality of fibers making up the scaffold, the scaffold further comprising a second structure of deposited electrospun fibers, the second polymeric plurality of fibers overlaid on the first polymeric plurality of fibers, the second polymeric plurality of fibers comprising one or more portions with a higher deposition of fibers than one or more portions of the first polymeric plurality of fibers, the second structure of deposited electrospun fibers comprising the plurality of deposited electrospun fibers configured to provide structural reinforcement for a second period of time upon application of the three-dimensional electrospun biomedical patch to the tissue, wherein the second period of time is less than twelve months; the plurality of deposited electrospun fibers connecting the first polymeric plurality of fibers and the second polymeric plurality of fibers, the plurality of deposited electrospun fibers comprising a first set of deposited electrospun fibers generated by electrospinning a first polymer composition and a second set of deposited electrospun fibers generated by electrospinning a second polymer composition, wherein the first set of deposited electrospun fibers and the second set of deposited electrospun fibers are entangled, wherein the first set of deposited electrospun fibers and the second set of deposited electrospun fibers are bioresorbable; and a plurality of voids, the plurality of voids comprising one or more voids between 10 μm and 10 cm in length, wherein the three-dimensional electrospun biomedical patch is sufficiently pliable and resistant to tearing to enable movement of the three-dimensional electrospun biomedical patch with the tissue.
 32. The three-dimensional electrospun biomedical patch of claim 31, further comprising a spatial arrangement formed by one or more of the plurality of deposited electrospun fibers.
 33. The three-dimensional electrospun biomedical patch of claim 32, wherein the spatial arrangement comprises an asymmetrical arrangement.
 34. The three-dimensional electrospun biomedical patch of claim 32, wherein the spatial arrangement comprises a repeating pattern.
 35. The three-dimensional electrospun biomedical patch of claim 32, wherein the spatial arrangement is formed by overlaying the second polymeric plurality of fibers on the first polymeric plurality of fibers.
 36. The three-dimensional electrospun biomedical patch of claim 31, wherein the tissue comprises skin.
 37. The three-dimensional electrospun biomedical patch of claim 31, wherein the tissue comprises one or more of skin, dura mater, heart valve leaflets, cardiac tissue, trachea, gastrointestinal tract, pericardium, muscle, connective tissue, intestinal tissue, stomach tissue, bone, gastrointestinal tract, or mucosa.
 38. The three-dimensional electrospun biomedical patch of claim 31, wherein the first polymer composition comprises poly(lactic-co-glycolic acid).
 39. The three-dimensional electrospun biomedical patch of claim 31, wherein the first polymer composition comprises glycolic acid, and wherein the second polymer composition comprises caprolactone.
 40. The three-dimensional electrospun biomedical patch of claim 31, wherein the second polymeric plurality of fibers is overlaid on the first polymeric plurality of fibers by depositing the second structure of deposited electrospun fibers on the first structure of deposited electrospun fibers.
 41. The three-dimensional electrospun biomedical patch of claim 31, further comprising one or more pores, wherein the one or more pores vary between 10 μm and 10 cm.
 42. A three-dimensional electrospun biomedical patch for facilitating tissue repair, the three-dimensional electrospun biomedical patch comprising: a first polymeric plurality of fibers making up a scaffold, the scaffold comprising a first structure of deposited electrospun fibers, the first structure of deposited electrospun fibers comprising a plurality of deposited electrospun fibers extending in a plurality of directions in three dimensions to facilitate cellular migration for a first period of time upon application of the three-dimensional electrospun biomedical patch to a tissue, wherein the first period of time is less than twelve months; a second polymeric plurality of fibers making up the scaffold, the scaffold further comprising a second structure of deposited electrospun fibers, the second polymeric plurality of fibers overlaid on the first polymeric plurality of fibers, the second polymeric plurality of fibers comprising one or more portions with a higher deposition of fibers than one or more portions of the first polymeric plurality of fibers, the second structure of deposited electrospun fibers comprising the plurality of deposited electrospun fibers configured to provide structural reinforcement for a second period of time upon application of the three-dimensional electrospun biomedical patch to the tissue, wherein the second period of time is less than twelve months; the plurality of deposited electrospun fibers connecting the first polymeric plurality of fibers and the second polymeric plurality of fibers, the plurality of deposited electrospun fibers comprising a first set of deposited electrospun fibers generated by electrospinning a first polymer composition and a second set of deposited electrospun fibers generated by electrospinning a second polymer composition, wherein the first set of deposited electrospun fibers and the second set of deposited electrospun fibers are entangled, wherein the first set of deposited electrospun fibers and the second set of deposited electrospun fibers are bioresorbable; and a plurality of pores, the plurality of pores comprising one or more pores between 10 μm and 10 cm in length, wherein the three-dimensional electrospun biomedical patch is sufficiently pliable and resistant to tearing to enable movement of the three-dimensional electrospun biomedical patch with the tissue.
 43. The three-dimensional electrospun biomedical patch of claim 42, further comprising a spatial arrangement formed by one or more of the plurality of deposited electrospun fibers.
 44. The three-dimensional electrospun biomedical patch of claim 43, wherein the spatial arrangement comprises an asymmetrical arrangement.
 45. The three-dimensional electrospun biomedical patch of claim 43, wherein the spatial arrangement comprises a repeating pattern.
 46. The three-dimensional electrospun biomedical patch of claim 43, wherein the spatial arrangement comprises a symmetric arrangement.
 47. The three-dimensional electrospun biomedical patch of claim 43, wherein the spatial arrangement is formed by overlaying the second polymeric plurality of fibers on the first polymeric plurality of fibers.
 48. The three-dimensional electrospun biomedical patch of claim 42, wherein the tissue comprises skin.
 49. The three-dimensional electrospun biomedical patch of claim 42, wherein the tissue comprises one or more of skin, dura mater, heart valve leaflets, cardiac tissue, trachea, gastrointestinal tract, pericardium, muscle, connective tissue, intestinal tissue, stomach tissue, bone, gastrointestinal tract, or mucosa.
 50. The three-dimensional electrospun biomedical patch of claim 42, wherein the first polymer composition comprises poly(lactic-co-glycolic acid).
 51. The three-dimensional electrospun biomedical patch of claim 42, wherein the first polymer composition comprises glycolic acid, and wherein the second polymer composition comprises caprolactone.
 52. A three-dimensional electrospun biomedical patch for facilitating tissue repair, the three-dimensional electrospun biomedical patch comprising: a first polymeric plurality of fibers making up a scaffold, the scaffold comprising a first structure of deposited electrospun fibers, the first structure of deposited electrospun fibers comprising a plurality of deposited electrospun fibers extending in a plurality of directions in three dimensions to facilitate cellular migration for a first period of time upon application of the three-dimensional electrospun biomedical patch to a tissue, wherein the first period of time is less than twelve months; a second polymeric plurality of fibers making up the scaffold, the scaffold further comprising a second structure of deposited electrospun fibers, the second polymeric plurality of fibers overlaid on the first polymeric plurality of fibers, the second polymeric plurality of fibers comprising one or more portions with a higher deposition of fibers than one or more portions of the first polymeric plurality of fibers, the second structure of deposited electrospun fibers comprising the plurality of deposited electrospun fibers configured to provide structural reinforcement for a second period of time upon application of the three-dimensional electrospun biomedical patch to the tissue, wherein the second period of time is less than twelve months; and the plurality of deposited electrospun fibers connecting the first polymeric plurality of fibers and the second polymeric plurality of fibers, the plurality of deposited electrospun fibers comprising a first set of deposited electrospun fibers generated by electrospinning a first polymer composition and a second set of deposited electrospun fibers generated by electrospinning a second polymer composition, wherein the first set of deposited electrospun fibers and the second set of deposited electrospun fibers are entangled, wherein the first set of deposited electrospun fibers and the second set of deposited electrospun fibers are bioresorbable wherein the plurality of deposited electrospun fibers are deposited in an arrangement comprising a plurality of void slits between 10 μm and 10 cm in length; wherein the three-dimensional electrospun biomedical patch is sufficiently pliable and resistant to tearing to enable movement of the three-dimensional electrospun biomedical patch with the tissue.
 53. The three-dimensional electrospun biomedical patch of claim 52, further comprising a spatial arrangement formed by one or more of the plurality of deposited electrospun fibers.
 54. The three-dimensional electrospun biomedical patch of claim 53, wherein the spatial arrangement comprises an asymmetrical arrangement.
 55. The three-dimensional electrospun biomedical patch of claim 53, wherein the spatial arrangement comprises a repeating pattern.
 56. The three-dimensional electrospun biomedical patch of claim 53, wherein the spatial arrangement comprises a symmetric pattern.
 57. The three-dimensional electrospun biomedical patch of claim 53, wherein the spatial arrangement is formed by overlaying the second polymeric plurality of fibers on the first polymeric plurality of fibers.
 58. The three-dimensional electrospun biomedical patch of claim 52, wherein the tissue comprises skin.
 59. The three-dimensional electrospun biomedical patch of claim 52, wherein the tissue comprises one or more of skin, dura mater, heart valve leaflets, cardiac tissue, trachea, gastrointestinal tract, pericardium, muscle, connective tissue, intestinal tissue, stomach tissue, bone, gastrointestinal tract, or mucosa.
 60. The three-dimensional electrospun biomedical patch of claim 52, wherein the first polymer composition comprises poly(lactic-co-glycolic acid).
 61. The three-dimensional electrospun biomedical patch of claim 52, wherein the first polymer composition comprises glycolic acid, and wherein the second polymer composition comprises caprolactone. 